Vd Values Research Articles

Estimation of the volume of distribution of some pharmacologically important compounds from their structural descriptors

Quantitative structure-activity relationship (QSAR) approaches were used to estimate the volume of distribution (Vd) using an artificial neural network (ANN). The data set consisted of the volume of distribution of 129 pharmacologically important compounds, i.e., benzodiazepines, barbiturates, NSAIDs, tricyclic anti-depressants and some antibiotics, such as betalactams, tetracyclines and quinolones. The descriptors, which were selected by stepwise variable selection methods, were: the Moriguchi octanol-water partition coefficient; the 3D-MoRSEsignal 30, weighted by atomic van der Waals volumes; the fragmentbased polar surface area; the d COMMA2 value, weighted by atomic masses; the Geary autocorrelation, weighted by the atomic Sanderson electronegativities; the 3D-MoRSE - signal 02, weighted by atomic masses, and the Geary autocorrelation - lag 5, weighted by the atomic van der Waals volumes. These descriptors were used as inputs for developing multiple linear regressions (MLR) and artificial neural network models as linear and non-linear feature mapping techniques, respectively. The standard errors in the estimation of Vd by the MLR model were: 0.104, 0.103 and 0.076 and for the ANN model: 0.029, 0.087 and 0.082 for the training, internal and external validation test, respectively. The robustness of these models were also evaluated by the leave-5-out cross validation procedure, that gives the statistics Q2 = 0.72 for the MLR model and Q2 = 0.82 for the ANN model. Moreover, the results of the Y-randomization test revealed that there were no chance correlations among the data matrix. In conclusion, the results of this study indicate the applicability of the estimation of the Vd value of drugs from their structural molecular descriptors. Furthermore, the statistics of the developed models indicate the superiority of the ANN over the MLR model.

Clinical Pharmacokinetics of Paclitaxel Liposome with a New Route of Administration in Human Based on the Analysis with Ultra Performance Liquid Chromatography

We investigated the clinical pharmacokinetics of paclitaxel liposome with a new route of administration, which was intrapleural infusion, in nine advanced nonsmall-cell lung cancer (NSCLC) patients with malignant pleural effusions after a single administration. Paclitaxel concentrations were measured in pleural fluid and plasma using a simple and rapid ultra performance liquid chromatography (UPLC) method following intra- and inter-day validations. In subjects, AUC(0-96 h) values in pleural fluid and plasma were 17831 ± 6439 µg h/mL and 778 ± 328 µg h/mL, respectively, and T(max) values were initial time and 6.67 h after administration and the corresponding C(max) values were 558 ± 44 µg/mL and 12.89 ± 6.86 µg/mL, respectively. The T(1/2,IP), CL(IP) and Vd(IP) values in pleural fluid were 76 ± 48 h, 0.005 ± 0.002 L/h m(2) and 0.53 ± 0.23 L/m(2), respectively. The T(1/2,pla), CL(pla), and Vd(pla) values in plasma were 68.34 ± 56.74 h, 0.184 ± 0.080 L/h m(2), and 17.53 ± 16.57 L/m(2), respectively. However, some paclitaxel concentrations from several patients in plasma could not be detected at some designed time-points. Our results might offer new opportunities to design and determine individually appropriate therapeutic dosage regimens based on a pharmacokinetic profile.

Natural atmospheric noise statistics from VLF measurements in the eastern Mediterranean

[1] Very low frequency (VLF) (3–30 kHz) and extremely low frequency (ELF) (3–3000 Hz) electromagnetic transient signals and noise are generated by various natural and anthropogenic processes. On a global basis by far the most significant source is ELF/VLF radiation from lightning propagating in the Earth-ionosphere waveguide. This atmospheric “noise,” originating essentially from lightning discharges, is the main source of interference for VLF/LF telecommunications. One of the statistical measures that is used to define the properties of low-frequency radio noise is the voltage deviation Vd, which is a measure of the impulsiveness of the noise that is widely used to characterize radio noise, particularly in the International Radio Consultative Committee reports. In this paper we present atmospheric noise statistics based on VLF measurements at different temporal resolution (from minutes to seasonal variations). For the first time we present analysis of the statistical parameters of Vd from continuous broadband VLF measurements for a period extending more than 1 year. Our analysis shows that the long-term observed Vd characteristics can be reasonably estimated as the sum of two Gaussians distribution functions, while the hourly and seasonal distributions of Vd values can be fitted using a single Gaussian distribution with different mean and variance values.

Determination of mass transfer rates and deposition levels of polycyclic aromatic hydrocarbons (PAHs) using a modified water surface sampler

There are different approaches to determine dry deposition velocities (Vd) and mass transfer coefficients (KG) of individual polycyclic aromatic hydrocarbons (PAHs). A modified water surface sampler (MWSS) and a high volume air sampler were concurrently used to determine Vd and KG in this study. Ambient air and deposition samples were collected from August 2004 to May 2005 in Bursa, Turkey. The mean particle-phase dry deposition flux of PAHs was 890±520 ng/m2 d, while the mean gas-phase PAH flux was 5 060±4 260 ng/m2 d. The ratio between fluxes and air concentration values was used in calculation of Vd and KG. The average calculated Vd and KG values for PAH compounds were 0.52±0.36cm/s and 0.69±0.41cm/s, respectively. Despite the fluctuation on seasonal atmospheric concentrations due to regional sources and meteorological conditions, there was no significant difference on deposition velocities and mass transfer rates. KG was also calculated using some models reported in the literature and models developed using the MWSS. The predicted KG determined by models developed using the MWSS was 0.59±0.02cm/s showing a close agreement with the experimentally measured values.

Plasma pharmacokinetics and milk levels of ceftriaxone following single intravenous administration in healthy and endometritic cows

Pharmacokinetics and milk levels of ceftriaxone were studied in healthy and endometritic cows following single intravenous administration. The drug was detected up to 8 h of dosing in plasma of healthy and endometritic cows and the drug disposition followed three-compartment open model. The values of Vd(area), AUC, t(1/2beta), Cl(B), MRT and P/C ratio were 0.50 +/- 0.19 L.kg(-1), 62.2 +/- 23.3 microg.ml(-1).h, 1.02 +/- 0.07 h, 0.30 +/- 0.09 L.kg(-1).h(-1), 1.55 +/- 0.25 h and 0.52 +/- 0.27, respectively, in healthy and 1.55 +/- 0.52 L.kg(-1), 37.0 +/- 17.1 microg.ml(-1).h, 1.56 +/- 0.25 h, 0.56 +/- 0.14 L.kg(-1).h(-1), 2.14 +/- 0.34 h and 1.44 +/- 0.60, respectively, in endometritic cows. The drug was detected in milk for 36 h after administration. For MIC(90) of 0.5 microg.ml(-1) the most appropriate dosage for ceftriaxone, would be 9.0 mg.kg(-1) repeated at 6 h intervals for the treatment of endometritis in cows.

Influence of Solution Conductivity on Contact Glow Discharge Electrolysis

Using a thin platinum anode in contact with an electrolytic solution, normal electrolysis develops spontaneously to contact glow discharge electrolysis (CGDE) at sufficiently high voltage. During this transition, midpoint voltage (VD) is an important critical value. From VD on, plasma is sustained by direct current glow discharge between the electrode and the electrolyte surface. And H2O2 is the main non-faradaic yield. In this study, effects of conductivity on VD and the concentration of H2O2 have been investigated in Na2SO4 and NaCl solution. The results indicate that VD decreases with the increasing conductivity. And the value of VD and the concentration of H2O2 in NaCl solution are less than those in Na2SO4 solution. The concentration of H2O2 increases steadily and then decreases to maintain a stationary value.

Pharmacokinetic properties of indinavir in rat: some limitations of noncompartmental analysis

Background: Compartmental as well as noncompartmental analyses are used routinely in pharmacokinetic analysis. Materials and methods: Pharmacokinetic parameters of the anti-HIV agent, indinavir, have been determined in six male rats applying both the compartmental and the noncompartmental analysis. Results and discussion: A very slow declining phase was found in the indinavir plasma concentration profile using an extended sampling time period and applying a sensitive high-performance liquid chromatography assay method. This apparent terminal elimination phase can cause some significant errors when applying noncompartmental kinetic analysis to the data, with mean residence time (MRT) (544.2 ± 123.2 minutes), total systemic clearance (12.0 ± 2.1 mL/min/kg), and steady-state volume of distribution (Vd (ss)) (6.4 ± 1.0 L/kg) being highly different from the results of compartmental kinetic analysis (MRT, Cltotal, and Vd (ss) values of 23.7 ± 5.9 minutes, 35.18 ± 5.1 mL/min/kg, and 0.84 ± 0.28 L/kg, respectively). The parameters estimated by our noncompartmental approach were also significantly different from the results of the same type of data analysis reported in the literature. Conclusion: The differences in parameter estimations, while being a result of the extended plasma sampling period, which is recommended in noncompartmental analysis, support the priority of applying the compartmental analysis approach in the similar cases with some pre-assumptions, mainly ignoring the final apparent terminal elimination phase(s), very deep tissue, which involves very low drug concentrations.

Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats

The pharmacokinetics of piceatannol, pinosylvin and rhapontigenin were characterized in male Sprague-Dawley rats after single intravenous doses of 10 mg kg(-1) of each stilbene. Serial blood samples were collected via a catheter inserted into the right jugular vein and plasma samples were analysed for the selected stilbenes concentrations using reverse phase HPLC methods. After an acute intravenous dose of piceatannol, plasma AUC, urine t(1/2), CL and V(d) were 8.48+/-2.48 micro g h mL(-1), 19.88+/-5.66 h, 2.13+/-0.92 Lh(-1) kg(-1) and 10.76+/-2.88 L kg(-1)(mean+/-s.e.m.), respectively. The acute intravenous dose of pinosylvin yielded the plasma AUC, urine t(1/2), CL and V(d) values of 5.23+/-1.20 micro g h mL(-1), 13.13+/-2.05 h, 1.84+/-0.44 Lh(-1) kg(-1) and 2.29+/-0.56 L kg(-1)(mean+/-s.e.m.), respectively. Rhapontigenin intravenous dosing yielded the plasma AUC, urine t(1/2), CL and V(d) values of 8.39+/-0.10 micro g h mL(-1), 25.31+/-1.46 h, 1.18+/-0.035 Lh(-1) kg(-1) and 11.05+/-0.17 L kg(-1)(mean+/-s.e.m.), respectively. Each stilbene was extensively glucuronidated. These stilbenes were predominantly eliminated via non-urinary routes. All three stilbenes were highly distributed into tissues and were highly extracted by the liver. The detectable plasma half-lives of these xenobiotics appear to be relatively short. However, utilizing urinary concentration-time data, much longer elimination half-lives were evident. The estimates of oral bioavailability characterize these stilbenes as poorly bioavailable compounds.

Abstract B123: A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist in patients with advanced solid tumors

Abstract Background: R1507 is a fully human monoclonal antibody (IgG1) which selectively inhibits insulin-like growth factor receptor (IGF-1R). This phase I dose-escalation study in patients with advanced malignant solid tumors explored the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of R1507 manufactured using a Chinese hamster ovarian (CHO) cell line. Materials and Methods: R1507 was administered as a weekly (qW) or every 3 weeks (q3W) infusion until dose-limiting toxicity (DLT) or progressive disease were observed. Standard phase 1 inclusion criteria were used including adequate organ function, lack of uncontrolled intercurrent illnesses, and CD4 count >200/µl. Clinical assessments for safety and DLT, tumor assessments (every 6 weeks), PK and PD blood sampling were performed. Results: 36 pts were sequentially enrolled in dose levels 3 mg/kg (n= 3), 6 mg/kg (n= 13), 9 mg/kg (n= 7) qW or 16 mg/kg q3W (n= 13). Median pt age 52 yrs (range 18–80), M:F 21:15. Efficacy: 12 (33%) pts showed stable disease (mean duration 25 weeks, range 11–50 weeks) [prostate 4, sarcoma 4; adrenal, appendix, soft tissue, stomach 1 each], including 1 pt with prostate cancer on study for 72+ weeks. Safety: No DLT was observed and a maximum-tolerated dose (MTD) was not reached. Drug-related adverse events (AEs) by CTCAE were mostly grade 1 or 2: fatigue (11 pts), myalgia and nausea (5 each), hyperglycemia and muscle spasms (4 each), and anorexia (3). Fourteen pts had 20 SAEs, of which 2 were related to R1507: dyspnea and pyrexia. Six pts (17%) had 9 drug-related AEs grade ≥3: hyperglycemia and fatigue (2 each), diabetes mellitus, performance status decreased, weight decreased, thrombocytopenia, and dyspnea. PK: R1507 pharmacokinetics were nonlinear. After a single IV infusion, mean clearance (CL) decreased from ∼1000 mL/Day (CV=17.4%) at 3 mg/kg qW to 580 mL/Day (CV=25.7%) in the 16 mg/kg q3W dose group, suggesting saturable elimination. Volume of distribution (Vd) was relatively small, ranging from 5.8 – 7.8 L (CV=7.8–77%), and the mean half life was 10.5 days (CV=28.2%). At week 10, mean trough concentration at steady state (Css,min) was 40.5, 97.3, 127.5, and 90.3 ug/mL for the 3, 6, 9 qW and 16 mg/kg q3W groups respectively. Mean CL and Vd values calculated after multiple administrations were comparable to those calculated after single administration. PD: Dose proportional increase in total IGF-1 levels was observed after treatment with R1507. This increase was sustained until redosing at the 9 mg/kg qW dose level but not sustained in the 16 mg/kg q3W dose level. Conclusions: Treatment with R1507 is tolerable at the doses tested without DLT and has resulted in stable disease. The 9 mg/kg qW dose achieves sustained PK and PD effects and is currently being evaluated in phase II trials. Doses higher than 16 mg/kg q3W are being explored. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B123.

Hydrogen soil deposition at an urban site in Finland

Abstract. Hydrogen deposition velocities (vd) were estimated by field chamber measurements and model simulations. A closed-chamber method was used for soil deposition studies in Helsinki, Finland, at an urban park inhabited by broad-leaved trees. Radon tracer method was used to estimate the vd in nighttime when photochemical reactions were minimal and radon gas was concentrated in the shallow boundary layer due to exhalation from soil. A two-dimensional atmospheric model was used for the calculation of respective vd values and radon exhalation rates. The vd and radon exhalation rates were lower in winter than in summer according to all methods. The radon tracer method and the two-dimensional model results for hydrogen deposition velocity were in the range of 0.13 mm s−1 to 0.93 mm s−1 (radon tracer) and 0.12 mm s−1 to 0.61 mm s−1 (two-dimensional). The soil chamber results for vd were 0.00 mm s−1 to 0.70 mm s−1. Both models and chamber measurements revealed a relation between one week cumulative rain sum and deposition velocity. When precipitation events occurred a few days before the chamber measurements, lower vd values were observed. A snow cover also lowered vd.

Purification, characterization, and directed evolution study of a vitamin D 3 hydroxylase from Pseudonocardia autotrophica

Vitamin D 3 (VD 3) is a fat-soluble prohormone that plays a crucial role in bone metabolism, immunity, and control of cell proliferation and cell differentiation in mammals. The actinomycete Pseudonocardia autotrophica is capable of bioconversion of VD 3 into its physiologically active forms, namely, 25(OH)VD 3 or 1α,25(OH) 2VD 3. In this study, we isolated and characterized Vdh (vitamin D 3 hydroxylase), which hydroxylates VD 3 from P. autotrophica NBRC 12743. The vdh gene encodes a protein containing 403 amino acids with a molecular weight of 44,368 Da. This hydroxylase was found to be homologous with the P450 belonging to CYP107 family. Vdh had the same ratio of the V max values for VD 3 25-hydroxylation and 25(OH)VD 3 1α-hydroxylation, while other enzymes showed preferential regio-specific hydroxylation on VD 3. We characterized a collection of Vdh mutants obtained by random mutagenesis and obtained a Vdh-K1 mutant by the combination of four amino acid substitutions. Vdh-K1 showed one-order higher VD 3 25-hydroxylase activity than the wild-type enzyme. Biotransformation of VD 3 into 25(OH)VD 3 was successfully accomplished with a Vdh-expressed recombinant strain of actinobacterium Rhodococcus erythropolis. Vdh may be a useful enzyme for the production of physiologically active forms of VD 3 by a single cytochrome P450.

Spring and summertime diurnal surface ozone fluxes over the polar snow at Summit, Greenland

Continuous surface‐layer ozone flux measurements over the polar, year‐round snowpack at Summit, Greenland, resulted in deposition velocities (vd) that were smaller than most previous assumptions and model inputs. Substantial seasonal differences were seen in the ozone vd behavior. Spring, daytime ozone vd values showed low variability and were consistently ≤0.01 cm s−1. During summer, ozone fluxes displayed distinct diurnal cycles, and evidence for regular occurrences of bi‐directional behavior. Summer, daytime vd ranged between ∼0.01 to 0.07 cm s−1. Maximum summertime downward fluxes (ozone deposition) coincided with the hours of maximum solar radiation, i.e., noon–afternoon. During summer nighttime hours upward ozone fluxes were observed. These upward fluxes were interpreted as ozone production in a shallow layer near and above the snow surface with resulting upward ozone fluxes out of the shallow surface layer. Comparisons with published observations from temperate, midlatitude sites suggest different controls and behavior of ozone fluxes, and that ozone fluxes over snow depend on a myriad of parameters, including solar irradiance, snow chemical and physical properties, snowpack depth, and the type of substrate underneath the snow.

Disposition kinetics of sparfloxacin in healthy, hepatopathic, and nephropathic conditions in chicken after single intravenous administration

Objective:To study the variation of disposition kinetic values of sparfloxacin in healthy, hepatopathic, and nephropathic chickens after a single intravenous administration.Materials and Methods:Hepatotoxicity was induced by the administration of paracetamol (500 mg / kg / day, p.o. for seven days) and nephrotoxicity by uranyl nitrate (2.0 mg / kg / day dissolved in distilled water, i.v. for four days) in chickens. Disposition kinetic studies of sparfloxacin were investigated in healthy as well as hepatopathic and nephropathic birds after a single intravenous administration at 40 mg / kg body weight.Results:Maximum plasma concentration detected at 0.16 hour was 31.25 ± 2.95, 61.95 ±1.85, and 99.86 ± 2.21 μg / ml in healthy, hepatopathic, and nephropathic group, respectively. The drug could not be detected in the plasma of healthy birds beyond 12-hour period, while the same was detectable for 72 hour in the plasma of hepatopathic and nephropathic birds. The concentration of sparfloxacin was significantly (P < 0.01) higher in all the samples of hepathopathic and nephropathic birds compared to healthy birds. All the kinetic values were increased (P < 0.01) in the hepatopathic and nephropathic birds, except Vdarea and ClB values in hepatopathic Birds; while β and ClB values nephropathic birds were decreased significantly than that of healthy birds.Conclusions:The dose of sparfloxacin may be reduced in hepatopathic as well as nephropathic birds.

In silico quantitative structure pharmacokinetic relationship modeling of quinolones: Apparent volume of distribution

The use of in silico approaches for successful prediction of pharmacokinetic properties of compounds during new drug discovery has been increasing exponentially. These in silico models, for the prognosis of absorption, distribution, metabolism and excretion (ADME), are invariably based on the implementation of quantitative structure pharmacokinetic relationship (QSPR) techniques. The current study was conducted to investigate QSPR for apparent volume of distribution (Vd) in man among 24 Quinolone drugs employing an extrathermodynamic approach. It is vital to predict the Vd value of various drug leads during drug discovery so that compounds with poor bioavailability can be eliminated and those with an acceptable metabolic stability can be identified. Analysis of several thousands of QSPR correlations developed in the present study revealed an extremely high degree of cross-validated coefficient (Q2) using the leave-one-out method (P < 0.001). Logarithmic transformation tends to improve the correlations marginally (R2 = 0.936) but the inverse transform resulted in a distinct improvement in the correlation (R2 = 0.994). Electronic and topological parameters were found to primarily ascribe the variation in Vd. Overall, the diffusional interactions seem to play a major role in attributing Vd rather than the permeational ones.

ESTIMATION OF EARTHQUAKE INPUT LEVEL BASED ON DAMAGE OF STEEL GYMNASIUMS DUE TO THE 2004 MID NIIGATA PREFECTURE EARTHQUAKE

This paper presents result of estimation of earthquake input level to steel gymnasiums subjected to the 2004 Mid Niigata Prefecture Earthquake. The earthquake response analysis of 55 steel gymnasiums located in the stricken area of this earthquake was carried out to determine damage-causing earthquake input energy (Vd). In this paper, the Vd values of each gymnasium were compared with a pseudo-velocity response spectrum (Vs) prescribed in the Japanese building code. From the result of the analysis, the earthquake input level (Vd/Vs) to the gymnasiums in Kawaguchi-machi was estimated to be more than 1.5.

Structure of fast shocks in the presence of heat conduction

There are three types of magnetohydrodynamic (MHD) shocks: the fast shock, intermediate shock, and slow shock. The structure of slow shocks and intermediate shocks in the presence of heat conduction has been studied earlier [C. L. Tsai, R. H. Tsai, B. H. Wu, and L. C. Lee, Phys. Plasmas 9, 1185 (2002); C. L. Tsai, B. H. Wu, and L. C. Lee, Phys. Plasmas 12, 82501 (2005)]. Based on one-dimensional MHD numerical simulations with a heat conduction term, the evolution and structure of fast shocks are studied. The fast shock will form a foreshock in the presence of heat conduction. The foreshock is formed due to the heat flow from downstream to upstream and located in the immediate upstream of the main shock. In the steady state, the value of diffusion velocity Vd in the foreshock is found to nearly equal the upstream convection velocity in the fast shock frame. It is found that the density jump across the main shock in high Mach number case can be much larger than 4 in the early simulation time. However the density jump will gradually evolve to a value smaller than 4 at steady state. By using the modified Rankine-Hugoniot relations with heat flux, the density jump across the fast shock is examined for various upstream parameters. The results show that the calculated density jump with heat flux is very close to the simulation value and the density jump can far exceed the maximum value of 4 without heat conduction. The structure of foreshock and main shock is also studied under different plasma parameters, such as the heat conductivity K0, the ratio of upstream plasma pressure to magnetic pressure β1, Alfvén Mach number MA1, and the angle θ1 between shock normal and magnetic field. It is found that as the upstream shock parameters K0, β1, and MA1 increase or θ1 decreases, the width of foreshock Ld increases. The present results can be applied to fast shocks in the solar corona, solar wind, and magnetosphere, in which the heat conduction effects are important.

Validation of an Extracerebral Reference Region Approach for the Quantification of Brain Nicotinic Acetylcholine Receptors in Squirrel Monkeys with PET and 2-18F-Fluoro-A-85380

The aim of the present study was to explore the applicability of an extracerebral reference region for the quantification of cerebral receptors with PET. Male squirrel monkeys underwent quantitative PET studies of cerebral nicotinic acetylcholine receptors (nAChRs) with 2-(18)F-fluoro-A-85380 (2-FA). Data from dynamic PET scans were analyzed with various compartment- and non-compartment-based models, including a simplified reference tissue model (SRTM). Nondisplaceable volume-of-distribution (VDnd) values were determined in regions of interest after the blockade of 2-FA-specific binding by nicotine infusion. Binding potential values, estimated with the cerebellum and muscle as reference regions, were compared and the reproducibility of measurements was determined. One- and 2-tissue-compartment modeling and linear graphic analysis provided similar total volume-of-distribution (VD(T)) values for each studied region. VD(T) values were high in the thalamus, intermediate in the cortex and midbrain, and low in the cerebellum and muscle, consistent with the distribution pattern of nAChR containing alpha(4) and beta(2) receptor subunits (alpha(4)beta(2)*). The administration of nicotine at 2 mg/kg/d via an osmotic pump resulted in a nearly complete saturation of 2-FA-specific binding and led to very small changes in volumes of distribution in the cerebellum and muscle (-9% +/- 4% [mean +/- SEM] and 0% +/- 6%, respectively), suggesting limited specific binding of the radioligand in these areas. VD(T) measured in muscle in 15 monkeys was reasonably constant (3.0 +/- 0.2, with a coefficient of variation of 8%). VDnd in studied brain regions exceeded VD(T) in muscles by a factor of 1.3. With this factor and with muscle as a reference region, BP* values calculated for studied brain regions with the SRTM were in good agreement with those obtained with the cerebellum as a reference region. Significant correlations were observed between BP* values estimated with these 2 approaches. The reproducibilities of BP* measurements obtained with the 2 methods were comparable, with coefficients of variation of less than 11% and 13% for the thalamus and the cortex, respectively. These results suggest that the accurate quantification of nAChRs can be performed with 2-FA and a reference region outside the brain, providing a novel approach for the quantification of brain receptors when no suitable cerebral reference region is available.

Disposition kinetics and dosage regimen of levofloxacin on concomitant administration with paracetamol in crossbred calves

The disposition kinetics of levofloxacin was investigated in six male crossbred calves following single intravenous administration, at a dose of 4 mg/kg body weight, into the jugular vein subsequent to a single intramuscular injection of paracetamol (50 mg/kg). At 1 min after the injection of levofloxacin, the concentration of levofloxacin in plasma was 17.2 ± 0.36 µg/ml, which rapidly declined to 6.39 ± 0.16 µg/ml at 10 min. The drug level above the MIC90 in plasma, was detected for up to 10 h. Levofloxacin was rapidly distributed from blood to the tissue compartment as evidenced by the high values of the distribution coefficient, α (17.3 ± 1.65 /h) and the ratio of K12/K21 (1.83 ± 0.12). The values of AUC and Vdarea were 12.7 ± 0.12 µg.h/ml and 0.63 ± 0.01 l/kg. The high ratio of the AUC/MIC (126.9 ± 1.18) obtained in this study indicated the excellent antibacterial activity of levofloxacin in calves. The elimination half-life, MRT and total body clearance were 1.38 ± 0.01 h, 1.88 ± 0.01 h and 0.32 ± 0.003 l/kg/h, respectively. Based on the pharmacokinetic parameters, an appropriate intravenous dosage regimen for levofloxacin would be 5 mg/kg repeated at 24 h intervals when prescribed with paracetamol in calves.

Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study

Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR alpha4 or beta2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since alpha4beta2 nAChRs are known to be widely distributed within the entire brain. PET study using [18F]-F-A-85380, a high affinity agonist at the alpha4beta2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [(18)F]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In five patients who underwent an additional [(18)F]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal.

Increased brain uptake and brain to blood efflux transport of 14C-GABA in spontaneously hypertensive rats

The brain uptake and brain to blood efflux transport of 14C-GABA were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats using 20 min bilateral in situ brain perfusion in rats anesthetized using urethane. The volume of distribution (Vd) of 14C-GABA into cerebrospinal fluid (CSF) and brain regions (cortex, diencephalon, cerebellum, and brain stem) was significantly greater in SHR than in the corresponding regions in WKY rats ( p < 0.05). The estimated Vd value of 14C-GABA in CSF of SHR was 3.4 fold greater than that in WKY. Also compared to WKY, the Vd of 14C-GABA into cerebellum and cortex of SHR was 15.3 fold and 19.4 fold greater, respectively. Although the study of blood–brain barrier (BBB) integrity using 3H-mannitol revealed increased paracellular permeability at the brain capillaries of SHR when compared to WKY rats, this was found to be only partially responsible for the increased 14C-GABA uptake. The study of brain to blood efflux transport of 14C-GABA (after loading of brain with 14C-GABA by vascular perfusion) revealed that the half-time of elimination was significantly shorter in SHR (5.35 ± 0.66 min) than in WKY rats (14.83 ± 1.94 min), ( p < 0.001). HPLC analysis revealed that GABA concentrations in brain extracts and CSF of SHR were similar to those in WKY rats ( p > 0.05). The faster efflux in SHR might be, at least partially, responsible to compensate for increased uptake of this neurotransmitter and to preserve the protective function of BBB towards GABA. The protective function of the BCSFB towards GABA appears to be also preserved, since systemic infusion of GABA within a wide range of administered doses (0.004–5.00 mg/kg) produced an increase in GABA CSF concentration from around 0.5 μM to only 11 μM, and the obtained pattern of CSF GABA concentrations under these conditions did not differ between SHR and WKY rats, as revealed by HPLC.